tbuckley/cabot-search huggingface dataset:
Efficacy and safety of fruquintinib plus mFOLFOX6/FOLFIRI as first-line therapy in advanced metastatic colorectal cancer (mCRC).
Authors: Fuxiang Zhou, Wang Wen-bo, Ling Xia, Jing Dai, Han Wu, Lei Yang, Zhiguo Xiong, Jun Gong
Journal: Journal of Clinical Oncology (2023)

152 Background: Fruquintinib is a highly selective, and potent oral inhibitor of VEGF receptor 1, 2, 3 and has been recommended as a third-line treatment for mCRC patients (pts) in China because of its low toxicity, favorable ORR and survival benefit. FOLFOX/FOLFIRI is the preferred chemotherapy regimens of first-line for mCRC pts according to the NCCN guideline. Our study aimed to investigate the efficacy and safety of fruquintinib plus mFOLFOX6/FOLFIRI as first-line therapy in advanced mCRC pts. Methods: In this prospective, open-label, multi-center, single-arm phase 2 study (NCT05004441), pts who are diagnosed with unresectable mCRC, without prior systemic threated are recruited. RAS/BRAF status should be detected to exclude BRAF mutations before enrollment. Pts receive fruquintinib (3mg, QD, PO, Q4W) in combination with mFOLFOX6/FOLFIRI (Q2W) for up to 8 cycles. Pts with SD or above are followed by maintenance therapy (fruquintinib 3mg, QD, PO, Q4W, capecitabine 850mg/m 2 , BID, PO, D1-7, D15-21, Q4W) until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR), and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: Based on a data cutoff of September 2, 2022, 19 pts have been enrolled and treated, of which 13 pts have efficacy evaluation data. Media age is 60 (range: 50-73) years and 62% pts are male. 7 (54%) pts harboring RAS mutations while the remaining pts are wild-type (wt). 54% treated with mFOLFOX6. At a median follow-up of 5.9mo, all 13 pts are still on treatment. In best overall response assessment, the ORR is 77%, with 10 (77%) partial response (PR). Stable disease (SD) is 3 (23%) with a DCR of 100%. Median PFS has not yet reached. Safety profile exhibited that the regimen is tolerable and mainly grade 1/2. Grade 3 treatment-related adverse events (TRAEs) are neutrophil count decreased (23%), GGT increased (15%), leukopenia, AST increased and hypertension accounted for 1% respectively. No pts have serious adverse events. Conclusions: Combination treatment with fruquintinib plus mFOLFOX6/FOLFIRI as the first-line therapy followed by fruquintinib plus capecitabine maintenance in advanced mCRC pts shows promising efficacy and manageable safety profile. Longer follow up data with PFS, and OS will be presented. Clinical trial information: NCT05004441 .
Trimodality therapy with carboplatin/paclitaxel (CP) or FOLFOX (FFX) for esophageal/esogastric junctional cancer (EC/EGJ): Expanded safety and efficacy data from PROTECT.
Authors: Antoine Adenis, Guillaume Piessen, Samuel Le Sourd, Emilie Bogart, Amaury Paumier, Veronique Vendrely, Olivier Glehen, Laetitia Dahan, Victor Simmet, Damien Bergeat, Emmanuelle Samalin, Marion Chauvenet, Xavier Benoit d'Journo, Sandrine Hiret, Caroline Gronnier, Manon Baty, Diane Pannier, Julie Veziant, Marie-Cecile Le Deley, Xavier Mirabel
Journal: Journal of Clinical Oncology (2023)

370 Background: When combined to preoperative radiation therapy (RT), CP and FFX regimen provide both high complete resection (R0) rate for EC/EGJ cancer (Adenis, ASCO 2022). However, it appeared that neoadjuvant chemoradiation (nCRT) with CP is associated with a severe postoperative morbidity rate higher than expected. We present here the expanded safety and efficacy analyses from the PROTECT trial. Methods: PROTECT is a randomized, phase 2 trial which included stage II/III and ECOG PS ≤2 EC or Siewert I-II EGJ cancers. Patients (pts) received FFX or CP with concurrent RT (41.4Gy, 1.8Gy, 23 fractions), followed by surgery 4-8 weeks after completion of nCRT (Messager, BMC Cancer 2016). Co-primary endpoints were proportion of R0 rate and proportion of Clavien-Dindo severe postoperative morbidity. Main secondary endpoints were nCRT and postoperative safety (NCI CTCAE v.4), DFS and OS. Results: 41/50 (82%) and 39/50 (78 %) pts received the planned chemo cycles and concurrent RT in FFX and CP arms, respectively. Grade (gr.) 3–4 AEs related to nCRT (FFX 14/50, 28%; CP 14/50, 28%) occurring in ≥5% of pts included lymphopenia (n=3, 6%; n=4, 8%), neutropenia (n=1, 2%; n=3, 6%), fatigue (n=2, 4%; n=0) and esophagitis-related to RT (n=1, 2%; n=1, 2%). No death was reported during nCRT. Surgery (FFX and CP; mini invasive: 15 and 15, hybrid: 22 and 21, open: 7 and 12) was performed in 44 and 48 pts, in FFX and CP groups, respectively. The main gr. III-V surgical complications (Clavien-Dindo scale) occurring in ≥5% of pts included esophageal fistula (n=2/43 evaluable pts, 6%; 8/48, 17%), conduit necrosis (n=2, 5%; n=1, 2%), ARDS (n=3, 7%; n=3, 6%), pleural effusion (n=3, 7%; n=4, 8%), and haemorrhage (n=0; n=3, 6%). There were no postoperative deaths. With a median follow-up of 54m, median DFS were 12.3m and 20m (HR=0.84; 95%CI: 0.52-1.35; p=0.48) and median OS were 31.7m and 45.8m (HR=0.79; 95%CI: 0.47-1.32; p=0.36) in FFX and CP arms, respectively. Prognostic factors significantly associated to DFS in univariate analysis were: R0 resection, TRG1-2 and ypT0N0 status. Conclusions: A higher than expected number of severe esophageal fistula was observed in the CP arm. We could not demonstrate a significant benefit of CP compared to FFX in terms of survival outcomes, but the study was not primarily designed to specifically address this issue. Clinical trial information: NCT02359968 .
Analysis of survival outcomes in patients with pancreatic cancer who underwent upfront surgery.
Authors: Jae Hyup Jung, Jinkyeong Park, Jinwoo Ahn, Bomi Kim, Kwangrok Jung, Jong-Chan Lee, Jin-Hyeok Hwang, Jaihwan Kim
Journal: Journal of Clinical Oncology (2023)

679 Background: During the last decade, the survival outcomes of patients with pancreatic cancer (PC) have improved. We aimed to establish a model of which clinical factors contributed to improved survival in PC patients who underwent upfront surgery. Methods: Public data from the KOREA Health Insurance Review and Assessment (HIRA) database were collected. Medical records in a single tertiary center were also retrospectively reviewed between 2013 and 2018. Enrolled patients were those who underwent curative upfront surgery for PC. Results: A total of 12,146 patients in HIRA data and 267 patients in single-center data were collected. The overall survival (OS) rates have improved over the years in HIRA data and were reproduced in single-center data. Dividing the patients of single-center data into two periods (2013-2015 [119] vs. 2016-2018 [148]) based on the results of public data, the median OS was significantly different between the two periods (20.9 vs 32.1 months, p=0.003). According to multivariate regression analyses, young age (≤70 years), R0 resection, negative nodal involvement, adjuvant treatment, and palliative chemotherapy with FOLFIRINOX or gemcitabine plus nab-paclitaxel (GNP) were significantly associated with better OS. A survival prediction model was created using the beta-coefficients in cox regression analysis of the above five significant factors, and the c-index by bootstrap validation (resampling, 1500) was 0.7088. The weight scores were as follows: Age &gt;70 years, 1; R1 resection, 1; pN1, 1; pN2 stage, 3; no adjuvant treatment, 2; palliative chemotherapy with FOLFIRINOX and/or GNP, 3; without FOLFIRINOX or GNP, 5; no palliative chemotherapy, 5. Conclusions: Regarding the survival trends in patients with resected PC, we presented the recent improvement in survival over the years and suggested several clinical factors that contributed to it by different weights. Further studies are necessary for validation.[Table: see text]
Risk of gastric cancer among patients with newly diagnosed ulcerative colitis: A nationwide population-based study.
Authors: Hee Man Kim, Dae Ryong Kang, Hyun-Soo Kim
Journal: Journal of Clinical Oncology (2023)

471 Background: We aimed to assess gastric cancer risk in patients with newly diagnosed ulcerative colitis (UC). Methods: Based on claims data of the Korean National Health Insurance from January 2006 to December 2015, we identified 30,546 patients with UC and randomly selected 88,829 age- and sex-matched non-UC individuals (controls). Hazard ratios (HRs) adjusted for covariates were calculated using multivariate Cox proportional-hazards regression. Results: Overall, 77 (0.25%) patients with UC and 383 (0.43%) non-UC individuals developed gastric cancer during the period. HR of UC was 0.60 (95% CI: 0.47–0.77) for gastric cancer, compared to non-UC individuals. When stratified according to age and sex, HRs in 20-39, 40-59, and ≥ 60 years of age at diagnosis of UC were 0.19 (95% CI: 0.04–0.98), 0.65 (95% CI: 0.45–0.94), and 0.60 (95% CI: 0.49–0.80), and HR of male UC patients was 0.54 (95% CI: 0.41–0.73) for gastric cancer. However, among UC patients, multivariable analysis revealed that HR in ≥ 60 years of age at diagnosis of UC were 12.34 (95% CI: 2.23-68.16), consistent with old age as a risk factor of gastric cancer in general population. Conclusions: Patients with UC had a decreased gastric cancer risk compared with non-UC individuals. Further research is needed to elucidate the reason.
Neutrophil-to-lymphocyte ratio and clinical outcomes in liver resection for metastatic colorectal cancer.
Authors: Sarah Reddy, Joanna El Hajj, Georgios Karagkounis, Patricio M. Polanco, Matthew R. Porembka, Aravind Sanjeevaiah, Amy Little Jones, Salwan Al Mutar, Radhika Kainthla, Emina Huang, Syed Mohammad Ali Kazmi
Journal: Journal of Clinical Oncology (2023)

233 Background: The neutrophil-to-lymphocyte ratio (NLR) has been shown to correlate with overall and disease-free survival in patients with colorectal cancer. The data about prognostic value of the NLR in patients undergoing liver resection for colorectal liver metastases (CRLM) is limited. We aimed to describe the relationship between the NLR, overall survival and disease progression in patients who underwent liver resection for CRLM in a safety-net hospital. Methods: We identified patients who underwent liver resection with curative intent for metastatic colorectal cancer at a large safety net hospital between 2008 and 2020. All patients had a complete blood count with differential available within three months prior to resection. We compared patients who had a pre-operative NLR ≤3 with those who had a NLR &gt; 3, a cut-off based on ROC analysis. We used the Chi-squared statistic and t-test to compare the frequencies of categorical variables and the means of continuous variables, respectively. Multivariate survival analyses were performed using the Cox-regression model after adjusting for sex, age at liver resection, race/ethnicity, body mass index, insurance status, initial presentation of colorectal cancer (emergency room vs outpatient), primary malignancy (colon vs. rectal), temporality of CRLM (synchronous vs metachronous presentation with primary), staged vs simultaneous removal of primary mass and CRLM, number and size of liver CRLM, other metastatic sites at the time of liver resection, carcinoembryonic antigen (at initial diagnosis, before and after resection), and receipt of at least six months of peri-liver resection chemotherapy. Results: We identified 76 patients who underwent liver resection with curative intent for CRLM with a median follow up of 40.7 months. The population had a mean age of 56.2 (SD 9.9), was 50% female, and predominantly non-White (73.7%). Compared with patients who had a NLR ≤3 (N = 50), patients with a NLR &gt; 3 (N = 26) were more likely to be white (46.2% vs 16.0%) and have rectal cancer (61.5% vs 28.0%). In unadjusted analysis, patients with NLR &gt; 3 had 1.87 times (95% CI 1.01-3.47) increased risk of mortality, compared with patients who had an NLR ≤3. In adjusted analysis, patients with NLR &gt; 3 had 6.88 times (95% CI 1.61-29.42), increased risk of mortality, compared with patients who had an NLR ≤ 3. There was no significant difference in risk of CRLM recurrence or overall disease progression among patients with NLR ≤3 vs patients with NLR &gt; 3. Conclusions: An elevated pre-operative NLR &gt; 3 is a potential predictor of overall survival among patients undergoing liver resection for metastatic colorectal cancer. This widely available test may aid clinicians in pre-operative risk stratification.
Identification of a subpopulation of patients with gastric cancer responsive to PARP inhibitors.
Authors: Simona Corso, Annalisa Petrelli, Sabrina Rizzolio, Filippo Pietrantonio, Sara Bellomo, Matteo Benelli, Loris De Cecco, Dario Romagnoli, Violeta Serra, Benedetta Pellegrino, Silvia Giordano
Journal: Journal of Clinical Oncology (2023)

432 Background: Treatment with PARP inhibitors (PARPi) has been approved in some tumors bearing a deficient Homologous Recombination (HR) system. Despite negative results of clinical trials conducted on the overall population of gastric cancer (GC) patients, we wondered whether a PARPi therapeutic strategy might represent a window of opportunity for a subpopulation of these patients. 7-12% of gastric cancers exhibit a mutational signature associated with HR failure, suggesting that these patients might benefit from PARPi. Methods: To analyze responsiveness to PARPi we exploited a proprietary human Gastro-Esophageal Adenocarcinoma (GEA) annotated platform of Patient-Derived Xenografts (PDXs) and PDX-derived primary cells on which we performed in vivo and in vitro experiments. Results: We selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that treatment with PARPi was effective in PDXs harbouring BRCA2 germline mutations and somatic inactivation of the second allele in a microsatellite stable background. PARPi responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency and mutational signatures efficiently stratified responder vs non-responder PDXs. A retrospective analysis on 57 GEA patients showed that those carrying BRCA2 inactivating variants had longer PFS upon platinum-based regimens (used as proxy). In 5 out of 7 BRCA2 germline mutated patients we identified the p.K3326* variant, currently classified as “benign”. However, familial history of cancer, the absence of RAD51 foci in the tumor cells and a high HR deficiency score suggest a deleterious effect for this mutation in gastric cancer. Conclusions: PARP inhibition could represent a new therapeutic perspective for BRCA2 mutated and/or high HRD score GEA patients, including familial intestinal gastric cancer patients.
The prediction of pathological complete response after total neoadjuvant therapy for locally advanced rectal cancer using versatile liquid biopsy.
Authors: Akihisa Matsuda, Takeshi Yamada, Hiromichi Sonoda, Seiichi Shinji, Takuma Iwai, Kohki Takeda, Kazuhide Yonaga, Kohji Ueda, Sho Kuriyama, Toshimitsu Miyasaka, Shintaro Kanaka, Hiroshi Yoshida
Journal: Journal of Clinical Oncology (2023)

230 Background: Total neoadjuvant therapy (TNT) has conferred a dramatic paradigm shift in the treatment for locally advanced rectal cancer (LARC), which can prolong the survival associated with high pathological complete response (pCR) rate and introduce non-operative management (NOM). However, useful biomarkers predicting the treatment efficacy of TNT and the prognosis has not been developed. Our previous study demonstrated that volume of blood long- and short-fragments DNA ( &gt; 300 bp and &lt; 180 bp) in LINE-1 gene are derived from tumor cell necrosis, and normal cell apoptosis, and the ratio (LSR) could reflect tumor growth or shrinkage, and minimal residual disease. Methods: A total of 17 LARC patients receiving consolidation TNT consisting of short-course radiation (5Gy x 5days) and 4 courses of CapOX, followed by total mesorectal excision were included. Blood concentrations of long-, short-fragment DNA and LSR in neoadjuvant phase were serially measured at pre-treatment, every treatment cycle, and pre-operation by real-time PCR. Results: Median age of patients were 64 years old and 65% were female. Clinical stage (IIa/IIc/IIIb/IIIc) were 2/1/8/6, respectively. Down staging was shown in 88% of patients. Tumor regression grade (0/1a/1b/2/3(pCR)) were 1/2/3/34/7(41%), respectively. Only 44% of patients had elevated CEA levels before TNT, which indicates less usefulness as the biomarker. The dynamics of the LSR in the entire cohort showed the gradual decrease until pre-operative phase (decrease to 77.8%). The LSR change from pre-treatment (or just after SCRT) to early preoperative treatment phase (1 or 2 course after CapOX) was significantly greater in the pCR(+)(n = 7) than the pCR(-)(n = 10) groups (66.8% vs. 101%, p = 0.03). The AUC of ROC analysis was 0.72 (cut off: 66.8%). Conclusions: NGS based liquid biopsy is the gold standard for the cancer prediction and monitoring, but limitations such as unsatisfied sensitivity and high cost are still involved. However, LSR measurement has great benefits on those points. Early phase LSR measurement could be a good predictive marker for the response of TNT and might be clinically useful for optimizing the preoperative therapy.
Analysis of the role of tumor microenvironment on clinical outcomes of chemotherapy in patients with advanced gastric cancer using high plex digital spatial profiling.
Authors: Tae-Yong Kim, Hye Seung Lee, Jihong Bae, Yujun Park, Do-Youn Oh, Jeesun Yoon, Soo Kyung Nam, Yoonjin Kwak
Journal: Journal of Clinical Oncology (2023)

456 Background: Tumor consists of not only cancer cells but also various immune cells or stromal cells. And tumor microenvironment (TME) is known to be associated with response and resistance to treatment. However, the role of TME in the response to chemotherapy in advanced gastric cancer (AGC) remains unclear. We evaluated whether TME can affect the survival in patients with AGC who received first-line chemotherapy using high plex digital spatial profiling (DSP). Methods: Patients with AGC who received first-line chemotherapy were registered. Archival tumor tissue before first-line chemotherapy were obtained and tissue microarrays (TMAs) were made. Regions of interest (ROIs) were selected on each TMA and high plex DSP including RNA transcript was performed in all ROIs using GeoMx DSP (Whole Transcriptome Atlas) after masking by cytokeratin (CK) immunofluorescence. Differentially expressed gene (DEG), geneset enrichment analysis (GSEA), gene ontology (GO) and cell subsets were analyzed separately in CK-positive and CK-negative areas, using EdgeR, mSigDb, DAVID and CIBERSORT. Results: Thirty-three tumor tissues from 33 patients and 5 normal tissues were analyzed. All patients received fluoropyrimidine and platinum doublet chemotherapy. HER2+ was 15.2% and all with HER2+ AGC received trastuzumab plus chemotherapy. Five received nivolumab plus chemotherapy. Response rate was 48.5% and progression-free survival (PFS) was 9.8 months (95% CI, 6.85-NA). In CK-positive area, high expression of PIGR (polymeric Immunoglobulin receptor gene) (FDR q=0.013) and low expression of IFNE (FDR q=0.027) were associated with long PFS. Response to interferon beta (FDR q=0.044), cytokine-cytokine receptor interaction (FDR q=0.014) and antigen processing and presentation pathway (FDR q=0.015) were less activated in patients with long PFS in GO and GSEA. Although the density of CD8+ T cell did not affect PFS (6.9 vs. 10.8, p=0.25), high density of CX3CR1+memory CD8+T cells (Tmem) showed longer PFS (18.3 vs. 6.6 months, p=0.01), compared with low density of CX3CR1+CD8+Tmem. In CK-negative area, low density of CD8+ T cells were associated with longer PFS (6.3 vs. 18.3 months, p= 0.008). Conclusions: TME particularly in CK-positive area might affect survival for chemotherapy in AGC. PIGR and CX3CR1+CD8+Tmem were suggested as good candidate markers for predicting clinical outcomes of chemotherapy, indicating further analysis of TME will be needed especially in patients with AGC who received immune checkpoint inhibitors.
Tislelizumab combined with anlotinib and chemotherapy (XELOX) in the treatment of advanced gastric carcinoma: Preliminary results of a single-arm, open-label phase I/IIa trial (TALENT study).
Authors: Xiaofeng Chen, Deqiang Wang, Yuan Yuan, Jie Tang, Fen Guo, Yizhang Chen, Junli Ding, Tingting Hong, Binbin Lu, Wei Li, Rong Wang, Yitong Tian, Lanlan Pan, Jiaguang Zhang, Xinyi Zhang, Tongpeng Xu, Hao Xu, Yongqian Shu
Journal: Journal of Clinical Oncology (2023)

396 Background: PD-1 inhibitor combined with chemotherapy is one of the standard regimens for first line gastric. The addition of anti-vascularization agents has been reported to help improve the overall survival (OS) in GC/GEJC patients (pts) through vascular-normalization in the microenvironment. In this phase I/IIa study, we aim to explore the safety and efficacy of tislelizumab combined with anlotinib and XELOX (TAXE regimen) as first line treatment for advanced GC/GEJC. Methods: This prospective, multicenter, phase I/IIa study planned to enroll 9 patients in phase I and 57 patients in Phase IIa. The aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and safety of 8 mg, 10 mg or 12 mg anlotinib in combination with XELOX and tislelizumab. The maximum tolerable dosage (MTD) would be administered to all pts in phase II. The primary and objective response rate(ORR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), OS, and safety. The exploring endpoint was to evaluate the association between the efficacy and the expression of biomarkers including PD-L1, microsatellite instability profile, and genome stability (GS). Results: From march 2021 to August 2022, 38 pts were enrolled (9 pts in phase 1). Phase 1 was completed without dosage limiting toxicities (DLTs). 12mg anlotinib was recommended for phase 2. Thirty two (84.21%) pts had at least one treatment-related adverse events (TRAEs), and 7 patients (18.42%) had at least one grade 3/4 TRAEs. Anemia (15 pts, 39.47%), leukopenia (12 pts, 31.58%) and fatigue (10 pts, 26.32%) were the most common TRAEs. Two pts achieved complete response (CR), 20 pts achieved partial response (PR), and 7 pts achieved stable disease (SD). The ORR was 75.86% (95% CI: 57.89%-87.78%), and the DCR was 100%. Conclusions: The preliminary results of this Phase I/IIa trial by using tislelizumab combined with anlotinib and XELOX had shown great potential in improving the response rate in advanced GC/GEJC patients with manageable toxicity. Clinical trial information: NCT04963088 .